Oat cell carcinoma of the lung is a rapidly fatal disease and aggressive chemotherapy is warranted. These studies evaluated combination chemotherapy with active agents (cyclophosphamide, adriamycin, and VP 16-213, as the basic regimen and CCNU, methotrexate, vincristine and procarbazine as an alternating regimen). Immunotherapy with MER was shown in a previous study not to be useful for response rate, duration or survival. Thirty-nine evaluable patients were entered onto the first study with the base combination, and the median duration of survival on this study will be greater than one year. Previously irradiated patients did less well than previously untreated patients, and the complete plus partial remission rate overall was 78%. For previously untreated patients, the complete plus partial response rate was 90%. Nine of the patients on that study continue on therapy beyond one year, and two patients are beyond two years and off all drugs for 8 and 5 months respectively. The subsequent study seeks to improve the complete remission rate and duration of response and survival by utilizing an alternating non-cross-resistant combination therapy program. Thirty-seven patients have been entered onto the second study, and preliminary evaluation shows no difference in the response rate. It is too early to develop stable survival data. Toxicity in these studies was manageable by dose modification.